title: PAX3-FOXO1 induces up-regulation of Noxa sensitizing alveolar rhabdomyosarcoma cells to apoptosis.
abstract: Alveolar rhabdomyosarcoma (ARMS) has a much poorer prognosis than the more common embryonal subtype. Most ARMS tumors characteristically possess a specific genomic translocation between the genes of PAX3/7 and FOXO1 (FKHR), which forms fusion proteins possessing the DNA binding domains of PAX3/7 and the more transcriptionally potent transactivation domain of FOXO1. We have shown that the proapoptotic BH3-only family member Noxa is upregulated by the PAX3-FOXO1 fusion transcription factor in a p53-independent manner. The increased expression of Noxa renders PAX3-FOXO1-expressing cells more susceptible to apoptosis induced by a γ-secretase inhibitor (GSI1, Z-LLNle-CHO), the proteasome inhibitor bortezomib, and BH3 mimetic ABT-737. Apoptosis in response to bortezomib can be overcome by shRNA knockdown of Noxa. In vivo treatment with bortezomib reduced the growth of tumors derived from a PAX3-FOXO1-expressing primary myoblast tumor model and RH41 xenografts. We therefore demonstrate that PAX3-FOXO1 up-regulation of Noxa represents an unanticipated aspect of ARMS tumor biology that creates a therapeutic window to allow induction of apoptosis in ARMS cells.
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Amy D
authors.initials: AD
authors.lastname: Marshall
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Picchione
authors.forename: Ramon I Klein
authors.initials: RI
authors.lastname: Geltink
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Grosveld
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001713:Biphenyl Compounds / Q000494:pharmacology; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D001897:Boronic Acids; D009596:Nitrophenols; D009842:Oligopeptides; D015514:Oncogene Proteins, Fusion; C471563:PAX3-FOXO1A fusion protein, human; C498702:PMAIP1 protein, human; D051761:Paired Box Transcription Factors; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; D000069286:Bortezomib